The taxane drugs, paclitaxel and docetaxel, are front-line chemotherapeutic agents used in the treatment of breast, ovarian and lung cancers. Despite their wide-spread use there are substantial shortcomings, and include myelosuppression, neurotoxicity and the frequent development of resistance (McGrogan et al., 2008; Perez, 1999).
Improvements to taxane-based therapies are hampered by a lack of mechanistic knowledge regarding its therapeutic activity: taxanes alter microtubule dynamics and cause arrest at the G2/M phase of cell cycle (Jordan et al., 1993; Yvon et al., 1999), but how this mitotic arrest results in cell death is not clear (Gascoigne and Taylor, 2009; Pellegrini and Budman, 2005; Weaver and Cleveland, 2005).
Mechanistic insights into taxane-induced cytotoxicity will have two major clinical benefits.
Firstly, each effector molecule has the potential to predict taxane responsiveness in breast cancer patients. Identification of predictive markers is of major importance, since currently there is no rational selection of those patients most likely to benefit from taxane therapy (Aapro, 2001; Noguchi, 2006).
Secondly, knowledge of the protein-interaction networks that modulate cellular responses to taxanes may identify targets for future drug development or combination therapy.
The literature suggests that paclitaxel-induced cell death converges on the mitochondria and is regulated by the Bcl-2 family of proteins. Paclitaxel-induced mitochondrial dysfunction is initiated by the BH3-only Bcl-2 family member Bim, as demonstrated in mouse model systems (Bouillet et al., 1999; Tan et al., 2005) and in certain human cell lines (Li et al., 2005; Sunters et al., 2003), but not breast cancer cell lines (Czernick et al., 2009). Species-specific and cell-type specific differences likely dictate which signaling molecules are activated in response to paclitaxel.
Bcl-XL/Bcl-2-associated death promoter (Bad) was originally identified as a Bcl-2-interacting protein (Yang et al., 1995). Bad mediates cell death in response to survival signal down-regulation and plays a key role in the growth factor regulated apoptosis of the developing nervous and immune systems (Datta et al., 2002; Zha et al., 1996). Growth factor stimulated kinases phosphorylate Bad at serine residues 112, 136 and 155 (mouse numbering), resulting in attenuation of Bad pro-death activity through sequestration by 14-3-3 proteins (Datta et al., 2000; Lizcano et al., 2000; Virdee et al., 2000; Zha et al., 1996). Loss of survival signaling results in dephosphorylation of Bad (Chiang et al., 2003; Klumpp et al., 2003; Roy et al., 2009), release from cytosolic 14-3-3 proteins (Datta et al., 2000; Peruzzi et al., 1999; Shimamura et al., 2000; Tan et al., 2000; Zha et al., 1996; Zhou et al., 2000), and subsequent migration to the mitochondria, where Bad functions as an anti-repressor to the pro-survival proteins Bcl-2, Bcl-XL and Bcl-w (Danial et al., 2008; Letai, 2008; Youle and Strasser, 2008).
Because Bad induces cell death through inhibition of anti-apoptotic proteins, Bad is designated as an “indirect” activator of apoptosis. It is through this mechanism that Bad induces apoptosis of breast cancer cells in response to loss of survival signaling mediated by epidermal growth factor (EGF) (Gilmore et al., 2002) and estrogen (Fernando and Wimalasena, 2004).
There remains a need, therefore, to provide compounds, compositions, method and/or kits for determining the benefit of chemotherapy treatment of cancer in a subject.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.